Role of IL-6-Induced Inflammation in Cerebral Aneurysm Pathogenesis

Introduction: Cerebral aneurysms (CA) carry significant morbidity and mortality especially when they rupture. Although endovascular approaches have decreased procedural morbidity, recurrence remains a concern with these techniques. Therefore, better understanding underlying pathogenesis of CA development can help develop new medical therapies which can complement endovascular techniques. Inflammation has been shown to play a pivotal role in pathogenesis of CA. Interleukin 6 (IL-6) has been identified in blood collected from human aneurysm dome. Further, elevated IL-6 has been linked with poor outcomes in patients with SAH. It is not known if IL-6 plays a direct role in CA development.

Methods: We used an established murine CA model using elastase. This model develops CAs as early as +d6. First, we wanted to establish if there is increased expression of IL-6 in the CA. CAs were induced on d0 and cerebral vessels at the base of the brain were collected on +d6 and +d14. mRNA expression was measured using nanostring. Further, to study a direct role of IL-6 in CA development, IL-6−/− knockout mice were used. CAs were induced on 0d. Surviving animals were euthanized on +d21 and assessed for incidence and size of CAs.

Results: There is elevated expression of IL-6 on +d6 compared with control. On +d14, IL-6 levels were still elevated but not as high as on +d6. This shows a critical role of IL-6 at least in the early phase of CA development. To confirm if IL-6 plays a direct role in CA development and progression, we used IL-6 −/− knockout mice. First, IL-6−/− knockout group demonstrated increased survival compared with control mice, 90% vs 50% at the end of 21-day period (+d21). Control group developed multiple large CAs. Incidence of CA formation in IL-6−/− knockout group was only 20% compared with 85% in control. When the CAs were analyzed in the 20% of IL-6 KO mice which developed aneurysms, the aneurysms were singular and much smaller, 28 mm in control versus 14 mm in IL-6 KO.

Conclusion: We have demonstrated for the first time, a direct role of IL-6 in pathogenesis of CA, confirming observations in humans. This has significant translational implications. IL-6 receptor (IL-6R) blockers such as Tocilizumab can be used to block the activity of IL-6 in the form of coated coils in humans which can suppress local activity of IL-6 in CAs in human, potentially suppressing recurrence.

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Artikel online veröffentlicht:
01. Februar 2023